Chronic Diarrhea

J�rg Steiner Germany

Initial approach

Diarrhea is one of the most common clinical problems for which dogs are presented to a veterinarian. Beyond that diarrhea is one of the most common clinical signs seen in dogs. Most cases of diarrhea consist of an isolated episode that does not affect the dog systemically. These patients are rarely presented to a veterinarian. Another group of dogs develops acute diarrhea that is associated with systemic clinical signs and requires aggressive diagnosis and therapy. Other cases are also acute but last only for a few days. Remission ensues without any treatment or with symptomatic therapy in many of these cases. However, there is also a large group of canine patients that have chronic diarrhea that need a proper medical work-up.

There are many different ways to approach the work-up of dogs with chronic diarrhea. Differences may be due to certain diagnostic modalities that may be available in some clinics but not in others, or they may be due to differences in clinical expertise of the clinician. Differences may also be due to a particularly common problem in a geographic region. In addition, the work-up needs to be guided by the urgency at hand. The degree of urgency is dependant on many factors, most importantly systemic clinical signs, rapid weight loss, presence and degree of hypoproteinemia, and finally, the tolerance by the owner. For example, rapid weight loss of a patient requires a more aggressive diagnostic approach than if there is no weight loss at all. Finally, differences in the work up can also be due to a difference in opinion.

As for any clinical problem, a careful history is important. It should include questions about the immediate and past clinical history of the patient that is being presented, the environment and the husbandry, especially as it relates to the diet. The clinical history should also include the history of other pets in the household. If the history does not reveal any specific indicators for a cause of the diarrhea, a reasonable initial approach includes careful fecal examination for evidence of parasitic infestation and treatment with a broad-spectrum anthelmintic agent such as fenbendazole regardless of the findings of the fecal exam.

The most important step for a proper diagnosis is determination whether the diarrhea is caused by a primary gastrointestinal disease or whether it is caused by a disorder of another organ system (see Figure 1). This goal can be achieved easiest by performing a complete blood count, a serum chemistry profile, and a urinalysis. Some additional serum should always be collected and frozen for future analyses.

Figure 1: Causes of chronic diarrhea

A complete blood count will help to identify endocrine disorders. For example, dogs with hypoadrenocorticism can show a lack of lymphopenia and eosinopenia, or may even have a lymphocytosis and eosinophilia, which is in contrast to many dogs that have an increased adrenocortical response because of any number of disease processes and show neutrophilia, monocytosis, lymphopenia, and eosinopenia. A CBC may also reveal anemia. The serum chemistry profile, together with specific gravity from the urinalysis is useful to rule out chronic renal failure. Hyperkalemia maybe present in dogs with acute oligouric renal failure. In addition, hyperkalemia and hyponatremia may be present in dogs with hypoadrenocorticism. However, it is important to note that not all dogs with hypoadrenocorticism show this abnormality. Some dogs do not lack mineralocorticoids and will not show electrolyte abnormalities.

Dogs that are suspected of having hypoadrenocorticism should be evaluated with an ACTH stimulation test. Hypoadrenocorticism, if untreated, can be a deadly disease and even a weak suspicion that hypoadrenocorticism might be present warrants performing this test. Results from the serum chemistry profile also help to rule out hepatic disease. Serum hepatic enzyme activities are very sensitive for hepatic disease. Unfortunately, they are not very specific and if abnormalities, especially mild ones, are detected the presence of hepatic disease needs to be confirmed using other diagnostic modalities.(1) Serum albumin concentration is rather insensitive for hepatic disease and is also not very specific. Serum bilirubin concentration can be increased in dogs with primary hepatic disease. However, it is not very sensitive, and more importantly, it is not specific. Dogs with this finding need to carefully evaluated for any evidence of hemolysis (PCV, slide agglutination, direct/indirect bilirubin), or extrahepatic cholestasis (abdominal ultrasonography).(2) If there is any doubt about the presence of hepatic disease serum pre- and postprandial bile acids need to be evaluated.(3) A new hepatic function test, ¹³C-aminopyrine demethylation blood test, is currently under investigation that may be more sensitive and specific than any other hepatic function test currently available for the dog.

Advanced work-up

Exocrine pancreatic disease can also cause chronic diarrhea and dogs with exocrine pancreatic insufficiency (EPI) often have diarrhea as the most important clinical sign.(4) In addition dogs with EPI often have weight loss, discoloration of feces, malodorous feces, and chronic skin disease.(4) However, some dogs only show chronic diarrhea. EPI in dogs is most commonly due to pancreatic acinar atrophy, a disease mainly seen in German Shepherd dogs. However, in other breeds, chronic pancreatitis, the most common cause of EPI in human beings and cats, may also cause EPI. Regardless of the cause, EPI can easily be diagnosed by serum cTLI concentration. This assay is available through many laboratories and should always be evaluated in conjunction with serum cobalamin and folate concentration.

Once secondary disorders have been ruled out, the type diarrhea should be characterized. In general, small and large bowel diarrhea can be distinguished. Dogs with small bowel diarrhea have an increased fecal volume but only a mildly increased frequency of defecation. Blood, if present, is digested, causing melena. Dogs with large bowel diarrhea often strain to defecate; they also often have fresh blood and an increased amount of mucous covering the feces. In addition, weight loss does not usually occur in dogs with large bowel diarrhea while dogs with small bowel diarrhea may or may not have weight loss. However, most dogs with clinical signs of large bowel diarrhea have more significant disease of the small bowel. In contrast to humans, isolated colitis is uncommon in dogs.

Many dogs with chronic diarrhea do have normal complete blood count and serum chemistry profile or only have non-specific changes such as a mild elevation of hepatic enzyme activities. These dogs should be worked up for primary gastrointestinal disease. As previously mentioned, fecal examination for parasite infestation and therapy with a broad-spectrum anthelmintic agent should be attempted before any further steps are taken if the overall condition of the dog allows this delay. Repeated zinc sulfate floatations are useful to diagnose Giardiasis.

Serum cobalamin and folate concentrations are of great diagnostic and therapeutic importance.(5) Serum folate concentration can be decreased in proximal small intestinal disorders, while serum cobalamin concentration can be decreased in distal small intestinal disorders and EPI. In dogs with diffuse small intestinal disorders, both serum folate and cobalamin concentrations can be decreased. Finally, a decreased serum cobalamin concentration and an increased serum folate concentration can be seen in canine patients with small intestinal bacterial overgrowth (SIBO). Folate and cobalamin are both water-soluble vitamins that are plentiful in canine and feline diets. However, dietary folate is poorly absorbed, because it occurs as folate polyglutamate and needs to be deconjugated to folate monoglutamate by folate deconjugase, a jejunal brush border enzyme. Folate monoglutamate is absorbed by specific carriers in the proximal small intestine. Therefore, longstanding and severe disorders of the proximal small intestine can lead to a depletion of folate body stores and a decreased serum folate concentration. In contrast, in cases of SIBO microorganisms in the small intestine synthesize folic acid, which can lead to an increase in folate absorption and in turn to an increased serum folate concentration. Dietary cobalamin is bound to dietary protein. In the stomach, dietary protein is partially digested by pepsin and HCl and cobalamin is released. However, cobalamin immediately binds to R-protein. The R-protein in turn is digested by pancreatic proteases in the small intestine. Free cobalamin binds to intrinsic factor released mostly in pancreatic juice. These cobalamin-intrinsic factor complexes are absorbed through specific receptors in the ileum. Therefore, severe and longstanding disorders of the distal small intestine as well as exocrine pancreatic insufficiency will lead to a depletion of cobalamin body stores and to a decreased serum cobalamin concentration. Finally, microorganisms, present in excessive numbers in the small intestine in patients with SIBO, will utilize cobalamin and compete with the host for dietary cobalamin. A low serum cobalamin in combination with an increased serum folate concentration is specific for SIBO and a therapeutic trial with an antimicrobial agent is indicated. Currently, the antibiotic agent of choice is tylosin at 10�15 mg/kg q12h for six weeks. Alternatively, metronidazole can also be used. An increased serum folate concentration alone is also indicative of SIBO and a trial therapy is appropriate. However, in both cases the dog should respond within approximately one week of therapy. Failure to show at least partial response within that period should initiate a further diagnostic workup.

Serum cobalamin is also of therapeutic interest. Cobalamin deficiency in human patients has been shown to cause villous atrophy, inflammatory infiltrates of the intestinal mucosa, cobalamin malabsorption, and other changes. Cats and dogs with severe cobalamin deficiency often do not respond to therapy of the underlying gastrointestinal disorder until cobalamin is supplemented. Since cobalamin deficiency causes cobalamin malabsorption oral supplementation is not efficacious in patients with severe cobalamin deficiency. In addition, multi-vitamin preparations do not contain sufficient amounts of cobalamin and pure cobalamin is needed for therapy. In dogs, 250�500 µg are given subcutaneously once a week for six weeks, followed by every other week for six weeks, one more dose a month after that, and a recheck a month after the last dose.

For all dogs that do not have secondary chronic diarrhea, parasitism, or SIBO, there are two choices: more diagnostic tests or a therapeutic trial. The choice depends on many factors but ultimately is dependant on the urgency of the case and the goals of the owner. If the dog does not have any systemic clinical signs and does not deteriorate, a therapeutic trial is reasonable. There are two basic approaches to an initial therapeutic trial. Many dogs with chronic diarrhea have dietary intolerance or dietary hypersensitivity. In either case, a dietary trial using a diet with a novel protein and a novel carbohydrate source are one option. Another option is to use one of the new diets that contain hydrolyzed proteins. The patient should show some response to a dietary trial one to two weeks after initiation, but complete remission could take up to six to eight weeks.

However, if the dog is not stable or quickly deteriorating, or if the owner wants to do anything possible regardless of cost or prognosis, more diagnostic tests should be performed immediately. Some clinicians prefer to do an abdominal ultrasound first because of its non-invasiveness. Abdominal ultrasonography can be useful to identify neoplastic or fungal lesions, to identify partial obstructions by foreign bodies or an intussusception, or to visualize mesenteric lymph nodes. Other clinicians prefer to perform a gastroduodenoscopy first since the diagnostic yield for this procedure is higher than for abdominal ultrasonography in most cases. However, it is also more invasive and does not allow visualization of the other abdominal structures.

A special scenario that deserves mentioning is the patient with panhypoproteinemia or hypoalbuminemia, with or without chronic diarrhea. These patients need to be carefully screened for possible hepatic disease and protein-losing nephropathy (PLN). Hepatic disease should be ruled out by serum chemistry profile and pre- and postprandial bile acids, while protein-losing nephropathy should be ruled out by performing a urine protein-creatinine ratio. If the dog does not have any evidence of hepatic disease or PLN, protein-losing enteropathy (PLE) can be confirmed by measuring fecal alpha₁-proteinase inhibitor concentration. This test is also useful to diagnose an increased fecal protein loss in dogs that have not yet developed panhypoproteinemia. For example, soft-coated Wheaten Terriers that have a familial PLE/PLN have increased fecal alpha-1-PI before any clinical signs are present.(6)There are other diagnostic tests that may help to diagnose primary gastrointestinal disorders in difficult cases. Gastrointestinal permeability and mucosal function testing is extremely sensitive and shows abnormalities long before histopathologic changes can be seen in biopsy specimens. Serum unconjugated bile acids and breath hydrogen testing can be useful in supporting a diagnosis of small intestinal bacterial overgrowth.

References

1.  Center SA. Diagnostic procedures for evaluation of hepatic disease. In: Guilford WG, Center SA, Strombeck DR, Williams DA, Meyer DJ, eds. Philadelphia: W.B. Saunders Company, 1996:130-88.

2.  Rothuizen J, Van den Brom WE, Fevery J. The origins and kinetics of bilirubin in dogs with hepatobiliary and haemolytic diseases. J.Hepatol. 1992;15:17-24.

3.  Center SA, Baldwin BH, Erb HN, Tennant BC. Bile acid concentrations in the diagnosis of hepatobiliary disease in the dog. J.Am.Vet Med.Assoc. 1985;187:935-40.

4.  Williams DA. Exocrine pancreatic insufficiency. Walth.Focus 1993;2:9-14.

5.  Batt RM, Morgan JO. Role of serum folate and vitamin B12 concentrations in the differentiation of small intestinal abnormalities in the dog. Res.Vet.Sci. 1982;32:17-22.

6.  Vaden SL, Sellon RK, Melgarejo LT, Williams DA, Trogdon MM, VanCamp SD et al. Evaluation of intestinal permeability and gluten sensitivity in Soft-Coated Wheaten Terriers with familial protein-losing enteropathy, protein-losing nephropathy, or both. Am.J.Vet.Res. 2000;61:518-24.